The overall goal of the Program Project structure is to provide an environment that fosters detailed, multi- disciplinary characterization of the development of virus-specific and cross-reactive (XR) CDS+ T cells, using the Epstein Barr virus (EBV) model of human infection. Each project in this Program Project is interdependent with regard to expertise, resources, and experimental design and requires access to high- quality clinical specimens and similar technologies. Core A will provide the necessary scientific leadership (including Internal and External Advisory Boards) and administrative and fiscal support to facilitate these multi-disciplinary, collaborative studies. These multidisciplinary studies will result in large and diverse data sets; experts in bioinformatics and biostatistics will not only assist in the development of an integrated database but will also help develop and apply appropriate analytical approaches. In the absence of a suitable animal model, human studies are essential. The University of Massachusetts Amherst (UMA) Health Services Acute Infectious Mononucleosis (AIM) Clinic provides essential clinical samples and constitutes one of a very few longitudinal AIM cohorts in the world. Over the years, we have altered clinical visit and sample collection schedules to address evolving scientific questions. While the AIM Clinic remains the main source of our clinical samples, the newly created UMA EBV Serosurveillance Cohort will allow us to obtain updated estimates of EBV seropositivity and seroconversion in college students. Work conducted over the past funding period has identified high frequencies of influenza and EBV XR CD8+ T cells in the circulation of a small group of individuals who remain EBV uninfected into their third decade of life and beyond. This has led to a novel hypothesis (i.e., that high frequencies of these cross-reactive CDS+ T cells might protect against EBV infection) and organization of a new cohort (EBV Seronegative; EBV-SN) that will be recruited to address this new hypothesis in the next funding period.